Human precision-cut liver slices as a model to test antifibrotic drugs in the early onset of liver fibrosis

Westra, Inge M.; Mutsaers, Henricus A M; Luangmonkong, Theerut; Hadi, Mackenzie; Oosterhuis, Dorenda; Jong, Koert P. de; Groothuis, Geny M. M.; Olinga, Peter

doi:10.1016/j.tiv.2016.05.012

Cited by 53 publications

(58 citation statements)

References 52 publications

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“…Whereas there have been some recent advances in the study of hepatic fibrosis in vitro using precision cut liver slices (PCLS) or spheroids (Leite et al, 2016;Thiele et al, 2015;Van de Bovenkamp et al, 2007;Westra et al, 2016), there still exist limitations in the application of these platforms to understand the progression of events underlying fibrogenesis. PCLS have a short life span ex vivo (generally <1 week) and develop early onset fibrogenic changes, irrespective of treatment, which may confound the interpretation of a causal relationship after compound exposure (Westra et al, 2016). As such, chronic exposure studies aimed at modeling progressive fibrogenic features over weeks to months have not been feasible with PCLS.…”

Section: Discussionmentioning

confidence: 99%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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Compound-induced liver injury leading to fibrosis remains a challenge for the development of an Adverse Outcome Pathway useful for human risk assessment. Latency to detection and lack of early, systematically detectable biomarkers make it difficult to characterize the dynamic and complex intercellular interactions that occur during progressive liver injury. Here, we demonstrate the utility of bioprinted tissue constructs comprising primary hepatocytes, hepatic stellate cells, and endothelial cells to model methotrexate-and thioacetamide-induced liver injury leading to fibrosis. Repeated, low-concentration exposure to these compounds enabled the detection and differentiation of multiple modes of liver injury, including hepatocellular damage, and progressive fibrogenesis characterized by the deposition and accumulation of fibrillar collagens in patterns analogous to those described in clinical samples obtained from patients with fibrotic liver injury. Transient cytokine production and upregulation of fibrosis-associated genes ACTA2 and COL1A1 mimics hallmark features of a classic wound-healing response. A surge in proinflammatory cytokines (eg, IL-8, IL-1b) during the early culture time period is followed by concentration-and treatment-dependent alterations in immunomodulatory and chemotactic cytokines such as IL-13, IL-6, and MCP-1. These combined data provide strong proof-of-concept that 3D bioprinted liver tissues can recapitulate drug-, chemical-, and TGF-b1-induced fibrogenesis at the cellular, molecular, and histological levels and underscore the value of the model for further exploration of compound-specific fibrogenic responses. This novel system will enable a more comprehensive characterization of key attributes unique to fibrogenic agents during the onset and progression of liver injury as well as mechanistic insights, thus improving compound risk assessment.Key words: liver fibrosis in vitro; 3D bioprinted liver; compound-induced liver injury.Chronic liver injury progressing to fibrosis and liver failure can result from a wide range of insults including drug or chemical exposure, metabolic disease, alcoholism, or viral infection, and is a major health burden worldwide with 2% of all deaths attributable to liver cirrhosis Murray et al., 2012). Whereas the major precipitating factors underlying drug-and chemicalinduced fibrosis have been gleaned from animal models, the key initiating and series of adaptive events that perpetuate this response, especially in humans, are still not well understood. Regardless of etiology, progressive fibrotic liver injury is

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Section: Discussionmentioning

confidence: 99%

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

et al. 2016

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“…Previously, rodent and human ex vivo model of liver fibrosis, precision‐cut liver slices (PCLS), have been successfully used to test the potency of a variety of putative antifibrotic compounds (Olinga and Schuppan, ; Westra et al, ; Westra et al, ). The main advantages of PCLS pertain to the facts that all cell types are preserved in their original environment and the possibility for studying in human tissues.…”

Section: Introductionmentioning

confidence: 99%

Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis

Luangmonkong

Suriguga

Bigaeva

et al. 2017

British J Pharmacology

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“…In human liver cells, it has been shown that it attenuates TGF‐β‐induced mRNA expression of α‐SMA and type I collagen . Also in human precision‐cut liver slices a reduction in the gene expression of type I collagen was observed following treatment with pirfenidone …”

Section: Regenerative Medicine To Attenuate Scarring and Muscle Fibrosismentioning

confidence: 99%

Tissue engineering strategies combining molecular targets against inflammation and fibrosis, and umbilical cord blood stem cells to improve hampered muscle and skin regeneration following cleft repair

Schreurs

Suttorp

Mutsaers

et al. 2019

Medicinal Research Reviews

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Cleft lip with or without cleft palate is a congenital deformity that occurs in about 1 of 700 newborns, affecting the dentition, bone, skin, muscles and mucosa in the orofacial region. A cleft can give rise to problems with maxillofacial growth, dental development, speech, and eating, and can also cause hearing impairment. Surgical repair of the lip may lead to impaired regeneration of muscle and skin, fibrosis, and scar formation. This may result in hampered facial growth and dental development affecting oral function and lip and nose esthetics. Therefore, secondary surgery to correct the scar is often indicated. We will discuss the molecular and cellular pathways involved in facial and lip myogenesis, muscle anatomy in the normal and cleft lip, and complications following surgery. The aim of this review is to outline a novel molecular and cellular strategy to improve musculature and skin regeneration and to reduce scar formation following cleft repair. Orofacial clefting can be diagnosed in the fetus through prenatal ultrasound screening and allows planning for the harvesting of umbilical cord blood stem cells upon birth. Tissue engineering techniques using these cord blood stem cells and molecular targeting of inflammation and fibrosis during surgery may promote tissue regeneration. We expect that this novel strategy improves both muscle and skin regeneration, resulting in better function and esthetics after cleft repair.

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Human precision-cut liver slices as a model to test antifibrotic drugs in the early onset of liver fibrosis

Cited by 53 publications

References 52 publications

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Editor’s Highlight: Modeling Compound-Induced FibrogenesisIn VitroUsing Three-Dimensional Bioprinted Human Liver Tissues

Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis

Tissue engineering strategies combining molecular targets against inflammation and fibrosis, and umbilical cord blood stem cells to improve hampered muscle and skin regeneration following cleft repair

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